Bronchiolitis Obliterans Syndrome (BOS), Bronchiolitis Obliterans Organizing Pneumonia (BOOP), and Other Late-Onset Noninfectious Pulmonary Complications following Allogeneic Hematopoietic Stem Cell Transplantation

AbstractPulmonary dysfunction is a significant complication following allogeneic hematopoietic stem cell transplantation (HSCT), and is associated with significant morbidity and mortality. Effective antimicrobial prophylaxis and treatment strategies have increased the incidence of noninfectious lung injury, which can occur in the early posttransplant period or in the months and years that follow. Late-onset noninfectious pulmonary complications are frequently encountered, but diagnostic criteria and terminology for these disorders can be confusing and therapeutic approaches are suboptimal. As a consequence, inaccurate diagnosis of these conditions may hamper the appropriate data collection, enrollment into clinical trials, and appropriate patient care. The purpose of this review is to clarify the pathogenesis and diagnostic criteria of representative conditions, such as bronchiolitis obliterans syndrome and bronchiolitis obliterans organizing pneumonia, and to discuss the appropriate diagnostic strategies and treatment options

Impact of unemployment on the living standards of families

Social security for the unemployed was not designed to cope either with large-scale or long-term unemployment and recent developments in the structure of unemployment and in social security policy give rise to concern for the living standards of the unemployed, especially the long-term unemployed. This article draws on data from the Family Finances Survey to assess the living standards of the unemployed after various durations of unemployment and compare these with the living standards of families with low incomes from work. The measures of living standards used are income, expenditure and the availability of consumer durables. The implications of the findings for social security policy are discussed

Impact of unemployment on the living standards of families

Social security for the unemployed was not designed to cope either with large-scale or long-term unemployment and recent developments in the structure of unemployment and in social security policy give rise to concern for the living standards of the unemployed, especially the long-term unemployed. This article draws on data from the Family Finances Survey to assess the living standards of the unemployed after various durations of unemployment and compare these with the living standards of families with low incomes from work. The measures of living standards used are income, expenditure and the availability of consumer durables. The implications of the findings for social security policy are discussed

Graft-versus-host disease of the skin: life and death on the epidermal edge

AbstractDespite impressive advances in the field of allogeneic hematopoietic transplantation, graft versus host disease (GVHD) remains a significant obstacle to be overcome; it would enhance the safety and efficacy of this life-saving therapy. This review provides a framework for understanding the molecular and cellular basis underlying GVHD. We propose a 3-phase model of GVHD that highlights the importance of the conditioning regimen on the recipient tissues administered prior to infusion of donor bone marrow inoculum. A novel skin explant model, designed to take into consideration the immunobiological consequences of conditioning regimens on resident host cells, is proposed to advance our understanding of GVHD and serve as a potential prognostic tool when allogeneic recipient/donor combinations are being contemplated in the clinic. Within this review, specific emphasis is placed on the importance of defining the apoptotic machinery engaged in epidermal keratinocytes triggered by both conditioning regimens, and by host resident and recruited immunocytes and soluble mediators produced at sites of injury. The review is completed with a working model for cutaneous GVHD. Although the skin is highlighted because of its accessibility for clinical observations and serial sampling opportunities, lessons learned from studies of cutaneous GVHD are likely to provide valuable insights into GVHD occurring in the gastrointestinal tract, lung, and liver. With new insights designed to better predict and prevent GVHD and novel agents designed to treat GVHD, overcoming this current impediment to successful bone marrow transplantation should become increasingly feasible

National Cancer Institute–National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on Late Effects After Pediatric Hematopoietic Cell Transplantation: Long-Term Organ Damage and Dysfunction

Long-term complications after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile

Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students

Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification

Defibrotide modulates pulmonary endothelial cell activation and protects against lung inflammation in pre-clinical models of LPS-induced lung injury and idiopathic pneumonia syndrome

IntroductionA multiple organ dysfunction syndrome (MODS) workshop convened by the National Institute of Child Health and Human Development in 2015 identified acute respiratory distress syndrome (ARDS) and complications of allogeneic blood and marrow transplantation (allo-BMT) as contributors to MODS in pediatric patients. Pulmonary dysfunction also remains a significant complication of allo-BMT. Idiopathic pneumonia syndrome (IPS) defines non-infectious, acute, lung injury that occurs post-transplant. Injury and activation to endothelial cells (ECs) contribute to each form of lung inflammation.MethodsTwo murine models were employed. In an ARDS model, naïve B6 mice receive an intravenous (i.v.) injection of lipopolysaccharide (LPS). In the established model of IPS, naïve B6D2F1 mice receive lethal total body irradiation followed by BMT from either allogeneic (B6) or syngeneic (B6D2F1) donors. Lung inflammation was subsequently assessed in each scenario.ResultsIntravenous injection of LPS to B6 mice resulted in enhanced mRNA expression of TNFα, IL-6, Ang-2, E-, and P-selectin in whole lung homogenates. The expression of Ang-2 in this context is regulated in part by TNFα. Additionally, EC activation was associated with increased total protein and cellularity in broncho-alveolar lavage fluid (BALF). Similar findings were noted during the development of experimental IPS. We hypothesized that interventions maintaining EC integrity would reduce the severity of ARDS and IPS. Defibrotide (DF) is FDA approved for the treatment of BMT patients with sinusoidal obstruction syndrome and renal or pulmonary dysfunction. DF stabilizes activated ECs and protect them from further injury. Intravenous administration of DF before and after LPS injection significantly reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P-selectin compared to controls. BALF showed decreased cellularity, reflecting less EC damage and leak. Allogeneic BMT mice were treated from day -1 through day 14 with DF intraperitoneally, and lungs were harvested at 3 weeks. Compared to controls, DF treatment reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P- selectin, BALF cellularity, and lung histopathology.ConclusionThe administration of DF modulates EC injury in models of ARDS and IPS. Cytokine inhibition in combination with agents that stabilize EC integrity may be an attractive strategy for patients in each setting

Discovery of the Galaxy Proximity Effect and Implications for Measurements of the Ionizing Background Radiation at Low Redshifts

We present an analysis of galaxy and QSO absorption line pairs toward 24 QSOs at redshifts between z~0.2 and 1 in an effort to establish the relationship between galaxies and absorption lines in physical proximity to QSOs. We demonstrate the existence of a galaxy proximity effect, in that galaxies in the vicinities of QSOs do not show the same incidence and extent of gaseous envelopes as galaxies far from QSOs. We show that the galaxy proximity effect exists to galaxy-QSO velocity separations of ~ 3000 km/s, much larger than the size of a typical cluster (~ 1000 km/s), i.e. it is more comparable to the scale of the sphere of influence of QSO ionizing radiation rather than the scale of galaxy-QSO clustering. This indicates that the QSO ionizing radiation rather than some dynamical effect from the cluster environment is responsible for the galaxy proximity effect. We combine previous findings that (1) many or most Lya absorption lines arise in extended galaxy envelopes, and (2) galaxies cluster around QSOs to show that the magnitude of the Lya forest proximity effect is underestimated. Consequently, determinations of the UV ionizing background intensity using the proximity effect are likely overestimated. We use the galaxy-QSO cross-correlation function measured from our data to estimate the magnitude of this overestimate and find that it could be as high as a factor of 20 at z<1. This can have strong implications for models of the origin and evolution of the ionizing background, and may indicate that QSOs produce sufficient ionizing flux at all redshifts to account for the entire background radiation field.Comment: 26 pages, 3 figures, to appear in ApJ, October 20, 200